Easy Immunology Lecture Series: 7 Tumor Immunology

Hinzugefügt: 2026-05-23

[00:00:00]and Alex.

[00:00:02]Oh, I heard it. Wow.

[00:00:07]Great. Then we can start. Do you know what we record today?

[00:00:12]>> Great. That's That's how it's intended.

[00:00:25]Welcome to Easy Minology. My name is Stefan and in today's video we want to look at a iminological topic that is very relevant also for the clinical practice and millions of people out there and uh I'm not going to tell you the topic at the moment because I want to work my way into it with my two colleagues. So as you might have realized if you have watched one of our videos before I never do this alone. I have again uh with me today Alex. Hi Alex.

[00:00:54]>> Hi Stefan.

[00:00:55]>> And Hannah. Hi Hannah. Hi Stefan.

[00:00:57]>> These two are uh both masters in biology and they help me by asking the questions you might have uh while watching this video which has proven very helpful and they also pay attention that I don't talk too much. So we will jump right into the topic with a clinical case presentation that comes out of my imagination but it is based more or less in reality. So this is something very typical that you might see as a doctor.

[00:01:25]So, we have a male patient that is 40 years old. He has two children, two small children, and he's always tired, and it doesn't even get better when he takes some rest. This is called fatigue.

[00:01:37]As a parent myself, I can tell you this could be caused by the two children. Uh, but here it isn't. He has also lost his appetite and lost already 14 pounds of weight. And you see, he's not a big guy.

[00:01:50]So losing 14 lbs without even trying is is something that is not not very good.

[00:01:57]He also has has frequent infections and he has something like this. Maybe one of you two have an idea what this could be.

[00:02:07]Yeah.

[00:02:12]>> Uh to me this looks like a swollen lymph node.

[00:02:15]>> Yeah, that's that's absolutely correct.

[00:02:17]So lymph nodes are secondary lymphoid tissues. We've made a video about it and they can increase quite massively in size when there is an infection going on because this is the place where the immune cells meet to start immune responses. So he has had this he also has pain in his chest. So there's also something wrong and he has a cough that doesn't go away. Okay. So he's coughing all the time and he is easily bruised and he has also this kind of of skin symptoms. So this is like small bleedings under the skin which we call uh pesh. He has fever and um he is also sweating at night and uh I've made the weight loss the fever and the night sweats bold because that's what the doctor calls a b symptomatic which is always a sign for a disease that is progressively getting worse. So something is not right with our patient and it is uh rather serious I would say. So maybe I can ask the two of them if they have any idea what what could be going on with our patient.

[00:03:28]Yeah, Alex, >> it's um seems like there's a chronic disease going on.

[00:03:35]>> Um and you said it already, it's probably really severe. So um it could be a tumor.

[00:03:42]>> Mhm.

[00:03:43]How did you how did you get to that conclusion?

[00:03:48]>> Um because when a tumor is growing. Um the whole body is working on that and it's costs a lot of energy um for the body to either fight or try to fight the tumor or the tumor is also growing and this is also los costs a lot of energy >> and uh this is causing the weight loss.

[00:04:09]>> Mhm. I know.

[00:04:12]>> Yes. And the swollen nymph nodes is a sign that the immune system is somehow involved. So the lymph flats are the the places where they the immune cells interact with each other and present um information to each other. So if it's swollen it means okay we have lots of immune cells in there. So this is also a hint that somehow the immune system is involved and yeah if it's a tumor or it can be some kind of other autoimmune disease I don't know.

[00:04:42]>> Mhm.

[00:04:43]>> But yeah this is I think Alex you're right.

[00:04:46]>> Yeah.

[00:04:48]Alex was was right. It is a tumor. It's a lymphoma. It's a tumorous disease where a part of the immune system is not working correctly. And we will look at uh what this means today. So today we will talk about tumor iminology. So tumor tumorous diseases cancer tumor iminology are big big fields. So we could fill a whole lecture series uh about the whole topic. Um but today we want to focus on giving a um rather broad overview what what a tumor is, how how it arises and then how we can use imminology to treat tumors because there's a revolution going on in tumor treatment at the moment and this is mostly caused by uh our better understanding of the immune system. So we will start it's rather more beat I know with uh talking about how relevant the topic actually is. So I have looked in into the database in Germany uh what people die from and uh I have ranked uh these these uh causes for for death in Germany and I would ask the two of them if they have any idea what could be the top three causes of death in Germany.

[00:06:05]Yeah. Hana, >> some kind of heart disease.

[00:06:09]>> Mhm.

[00:06:12]>> I would also say smoking is probably quite >> Mhm.

[00:06:17]>> quite good.

[00:06:18]>> Mhm. Anything else?

[00:06:24]Okay. Doesn't it's it's it's not a problem and we'll just look at it. So, here are the top three causes and also the um the difference between 2021, this was the the most up-to-date numbers I could find and 2011. So, so 10 years before you can see number one uh undisputed is eskeemic heart disease.

[00:06:47]So, this is exactly what what Hana and Alex were saying. So uh people die from from their heart not working and eskeemic means uh that the heart is under supplied or any organ is under supplied with oxygen and this can happen from not training enough from just being old uh from smoking and destroying uh your lungs. Uh so this is this is number one. Then we have Alzheimer's disease a disease that affects the brain and destroys uh the neurons in there.

[00:07:21]And we have COVID 19. Yeah, this is of course something that that didn't exist in 2011. Uh now it's number three already. And if you look at the other diseases, there are things like stroke.

[00:07:33]Uh so this is a clocking of a blood was vessel in the brain that causes massive damage in the brain. We have COPD. It's a uh inherited disease where your lung doesn't work correctly. you build a lot of very thick mucus and this is like a petri dish for bacteria. These people have frequent infections in the lung and die from it. Then you have chronic kidney disease, hypertensive heart disease. So this means having high blood pressure. This comes from not moving enough from just watching TV and eating all the the unhealthy foods we have. And then we have falls. So people die because they fall usually are they are pretty old at that point. and then falling is is the beginning of the end.

[00:08:20]So you should avoid this. So it's basically a sign for our societies becoming older and you see yes cancer is among uh the top 10 causes but it's not like in the first first places. So this is this is good and it shows how far we have come in in treating cancer. So uh as you will see today there is quite a bit of progress being made in treating cancers imunologically and this will mean in future probably very likely that cancer will be like a chronic disease that you can live with for most of your life ideally. Yeah. What you can also see what I find quite fascinating as an iminologist that there is just one infectious disease on there COVID 19. So we have also made tremendous tremendous progress in preventing death by well death from infectious diseases.

[00:09:17]So let's dive into the topic and I will start with two definitions cancer and tumor. So cancer is a disease that is caused by an uncontrolled division of abnormal cells in a part of your body or in your whole body. So we will look at in the next slides where this comes from, how this can be. And a tumor is a swelling of a part of the body that is generally without inflammation. So you can also have a typical inflammation. We have looked at this in previous videos.

[00:09:50]But these is usually uh with inflammation. So activation of the immune system whereas a typical tumor is without inflammation. And we will see today also why this is the case because tumors can regulate the immune system and this is again caused by an abnormal growth of tissue and it can be benign or malignant. So benign means uh it just growing in one place and doesn't do too much damage and malignant means um it uh causes quite a bit of damage and it also spreads in your body and will eventually kill you.

[00:10:24]So how does cancer arise? Cancer arise from normal cells turning into cancer cells and this is triggered by certain uh factors exttrinsic factors for example like carcinogens. These are um things substances that cause this change from normal to cancer cells. Then there is genetic mutation. This is an intrinsic cause which can again be triggered by for example carcinogens. So something in the DNA of the respective cell is changing. Then we have sun and other types of radiation. So a good part of of cancer that we have in our societies caused by not using enough sunscreen. And this causes then uh damage in your genes. And also viruses and some other infections can cause damage to your to your cells and turn them into cancer cells. And what happens actually on a molecular level is that so-called protoonco genes turn into enco genes. So an enco gene is a gene by definition that is uh changed in uh these cancer cells. And there are many different enko genes. And the protoonco genes are the the the normal versions of these genes that fulfill their normal function. And these protoonco genes are usually genes that are involved in regulating how the cell growth, how it proliferates, or how it turns into identical daughter cells. And how how the cell goes into apoptosis. So how it decides that okay my life is over now.

[00:12:01]I'm not useful anymore. I will just die in a controlled way. This is what apoptosis is. And examples are maybe transcription factors. So proteins that go into your nucleus and turn on and off a lot of different genes. Then we have uh gpases uh these are factors in the cells that regulate how the intricate network in the cell works and how these proteins and all the other things interact with each other. And then we have receptors for example for growth factors that signal via binding to the growth factor into the respective cell that it should should grow and divide and if this system is somehow damaged or changed it can lead to normal cells turning into cancer cells.

[00:12:48]So this this growth of cells and how cells divide is controlled by something that we call the cell cycle. This is how a a typical cell cycle looks like. You might have seen this in in high school. And it is divided into different phases. So normal cells in your body that fulfill their normal function like for example liver cells producing liver enzymes, they are in something that we call the G0ero phase. So they fulfill their normal function. And then if the cell decides, okay, I need to I need to divide. I need to make two or more cells out of myself. They leave this G0ero phase and they then uh prepare their genomic material for for the division and all the other stuff in the cell because basically if you have your one cell and then you want to turn into two identical daughter cells, everything in your cell needs to be duplicated and divided onto the two daughter cells.

[00:13:52]Then it starts in the so-called Sphase.

[00:13:56]This is the synthesis phase. There the DNA is uh replicated.

[00:14:02]Before the Sphase, your chromosomes contain of one DNA double strand. And after the Sphase, the strand was copied into two identical strands that are held together by a structure that we call a centromeare.

[00:14:18]Then uh the cells get some rest because this is an intensive and energy consuming process. And then they turn into the M phase. This is the mitosis phase.

[00:14:30]There first the all the chromosomes are lined up next to each other in the cell.

[00:14:35]It's fascinating. Certain spindles attached to the centrome and then they pull apart both u both parts of the chromosome which are called chromatids.

[00:14:48]And then um the cell divides in the middle and we have two small uh identical cells where the chromosomes again uh consist of just one chromatid.

[00:15:01]Then the cell goes into G1 phase where it recovers a little bit and then it can decide okay I can either switch to the G0ero phase and fulfill my normal function or I can grow again. That's why the the lower cell is a bit bigger.

[00:15:16]takes take some rest to recreate myself u while doing uh preparing for another um round of division. So this is the normal cell cycle and this results in one cell being able to turn into many identical daughter cells and this is this process the cell cycle is controlled by something that we call checkpoints. So there are three checkpoints in the cell cycle. The first one is between the G1 and the G0ero phase. Here the cell needs to decide do I need to um divide myself or do I just go into the G0ero phase or do I stay in the G0ero phase and fulfill my normal function. Then there is the second checkpoint. It's at the end of the G2 phase. And here the cell has gone through the Sphase and the G2 phase. And the cell then checks at the end of the G2 phase, did the duplication of the DNA and all the the components in the cell work? Am I really ready um to go into the mitosis phase? And then we have the last checkpoint that is at the end of or towards the end of the Mphase. And there the cell checks okay that the lining up of the chromosome works and are all the spindles attached to the central masses and can I really start pulling everything apart and turning into two cells because once you start there is there is no way back. Yeah, you will not get this this uh put together. So, so this these checkpoints make sure that this really complicated process works.

[00:16:56]And if now one of the the many proteins that control the uh cell cycle has has a malfunction, this cell will will be damaged and it might turn into a cancer cell. And in these cancer cells, all checkpoints are if you imagine this as a traffic light, they all put on green. So no matter if if the cell is ready or not, no matter if there have been mutations accumulated, the cell would just go through the uh cell cycle non-stop and will produce a lot of uh these damaged cancer cells. And if even if it starts with a single mutation, these cells are not not checked anymore.

[00:17:39]They divide uncontrollably all the time and this leads to even more mutations.

[00:17:44]So the genetic stability that is more or less guaranteed or should be guaranteed but the cell cycle is not given anymore.

[00:17:51]That's why cancer cells uh change quite quite dramatically genetically over time.

[00:17:58]So we now understand that this is uh happening by a deregulated cell cycle and if this growth of cells goes on for long enough they might form a tumor. So they will then uh form like a structure an organized more or less organized structure in your body that can be can be seen can be felt and can be can be found in diagnostic procedures that we call a tumor.

[00:18:27]I've brought an example of a cancerous disease and this is called uh the Philadelphia chromosome. uh this is a specific abnormality in patients that have a disease that is called chronic myoid leukemia CML. It's a disease where cells of your immune system divide uncontrollably and you can see this in diagnostic procedures by looking at the chromosomes. So there is uh something that you call a kariogram where you somehow fascinatingly can isolate the chromosomes. You can stain them and you can look at them under the microscope and then you find neatly arranged pairs of chromosomes because you usually have two of all the chromosomes except for your X and Y chromosome. And you can see that in patients that have this disease, chromosome 9 and 22 look a bit different because as you see in chromosome 9 on the left side, one one of the strands is a bit shorter. And in chromosome 22 on the left side, this strand is is a little bit longer. And what happens here is you have here the normal chromosome 9 and 22. And there is a chromosome break and a reshuffleling of the chromosome material. And part of um chromosome 9 gets then attached to 22 and the other way around. And this fascinatingly always happens in the same place and you get then this altered chromosome 22 where two genes are fused together. One is called the BCR gene, the B cell receptor gene. and it's part of the B cells, very important cells in the adaptive immune system. And the other one is the AL gene, the AEL kynise. And um the AEL kynise is one of these molecules that regulates the cell cycle. And this means that in these patients in B cells because the are the only cells that express the B cell receptor um this cell cycle is disrupted and then the B cells divide uncontrollably and cause a lot of damage in your body and then you develop this chronic myoid leukemia.

[00:20:44]As I said before, cancer can be or tumor cells can be uh benign or malignant.

[00:20:51]Here I brought you two to two example.

[00:20:53]One's called an adenoma. That is a benign uh change in uh some cells that make the epithelium of of some glands in your body and they just grow in one place.

[00:21:05]They form a tumor. But uh this tumor is happy to be there. Maybe doesn't even grow so fast and doesn't cause any damage. Then you have malignant types of cancers like adininocinomas and these might form a tumor. Uh but the cells also change. You see they look different. They are pretty degenerated compared to the cells that they arise from. And these cells also wander around in your body and they cause a lot of damage because they will spread in your body uncontrollably and they will form new new tumors in all your body. This is what we call a metastatic behavior. So that some cancerous cells spread from one body to to unconnected parts of your body and then you have not just one tumor that you can maybe uh cut out in a surgical procedure but then you have small tumors everywhere and in certain certain organs like the brain it's very difficult to cut something out without uh causing too much additional damage.

[00:22:10]So this is then very difficult to treat and this is this is a a big problem with these cancer diseases that you need to basically find them very early when it's just one small tumor then you have a good chance to to control it but once a tumor has spread it gets much more difficult. I would like to spend one slide on the classification of tumors. I know this can be much much more complicated but for a general first overview I think this is this is enough and this is good. So a cancerous tissue, so some part of your body that has turned into a a cancer or a tumor is called a malinoma. And they can be uh named either by the the affected organ.

[00:22:56]You might have heard this XY has lung cancer or brain tumor or kidney cancer.

[00:23:02]Or if you want to be more specific in a a medical sense, you can group the the tumors according to the type of degenerated tissue. And there are solid tumors where you can really find a tumor an accumulation of of tumor cells in your body. And they can be further subdivided into four types. So we have blastoomas. they uh arise from mutations in cells that form your your tissues and your organs. So these are the the the stem cells and this is what we often see in children unfortunately that these cells degenerate and I put it red here because this is usually a big problem. Yeah. So uh cancer in children is is not very frequent but when it is there it's usually not so not so good because these tissues have a very high potency to regenerate and to uh multiply and then if this happens we have very aggressive and very fast growing tumors that cannot be cannot be controlled usually. Then we have carcinoma. So where epithelial tissue turns into into cancer cells.

[00:24:16]This is also often malignant. And so the epithelial tissue is like the the if you want to make it very very simple is the upper upper layer of an organ or of uh of a blood vessel or something. And if this turns into cancer we call this a carinoma and this is often very malignant. Then we have sarcomas. there the supportive or connective tissue or fat tissue something like this turns turns into a a tumor. This is rarely malignant. So this is this is good. This can be treated quite quite good or maybe doesn't even need to be treated. And then we have teratoma where purip putin stem cells like germ cells turn into a tumor and this is also rarely malignant.

[00:25:00]And then we have systemic uh tumors. a systemic cancer where you don't necessarily find a solid tumor. So something you can feel and touch and can excise. But certain cells turn into tumor cells and they spread in your whole whole body. And there we have two types. You have leukemia where cells of the hematopoetic system. So cells that form or for example your blood or cells of the inate immune system turn into cancer cells. And then we have lymphoma where it's the lymphosytes the T and the B cells that turn into uh cancer cells.

[00:25:40]And this is what we observed in our clinical um example at the beginning and also in the Philadelphia chromosome.

[00:25:47]There was the B cells. Okay, this is just some some classification of tumors.

[00:25:52]And now I'd like to go a little bit into more uh into tumor biology with you. And this this can be studied in in mouse models. I know it's it's not the nicest thing to do, but uh this is what what we can do where you can establish models of these complex diseases. And what you can do is you can experimentally induce tumors by exposing the animals to chemicals, carcinogens, irradiation. So triggers that turn these protoonco genes into ankco genes. Then the mouse will develop a tumor and this tumor or the cells in these this tumor will grow uncontrolled and turn into a bigger tumor and then will kill a cell. Yes, Hannah.

[00:26:42]>> Why is the mouse pink?

[00:26:45]>> You are you are too smart. The mouse is pink. uh because uh I want to make a point out of it in uh in a one of the next slides, but it's good that you asked the Moses pink because it doesn't have an immune system. And there are certain models of of mice that do not have an immune system. They do not have hair. No, they are they are naked mice and that's why I made these mice pink.

[00:27:10]And uh most of the initial work on on cancer cells in mice was done on on these animals because as we will see as we will learn in a few slides usually your immune system is very good at uh eliminating tumors in very early stages.

[00:27:27]And therefore if you want to have a chance to reproducibly grow these tumors or induce these tumors in mice you need to use either very aggressive tumors or mice that do not have an immune system.

[00:27:40]Okay, you can also take uh live tumor cells and inject them into the mouse. It will form a tumor that will kill the mouse and you can then isolate some cells from that tumor again and transfer them into the next mouse and it will develop the same tumor. So once the the tumor cells are uh generated induced, they can be propagated more or less forever.

[00:28:08]However, if you destroy the tumor cells that you transfer, then the mouse will not develop a tumor and will live a normal and and happy life. So, this means the tumor cells have to be alive.

[00:28:20]It's not just a trigger of the tumor that that causes this uh this response, but uh the cells have to really be alive and have to divide.

[00:28:32]So, now we come to Hana's question. Um The tumor is recognized by the immune system and there are certain molecules on the surface of of all of our cells.

[00:28:45]So most of our cells that are called MHC molecules major histompatibility complex proteins and they are as we will also learn in the lecture about uh transplant rejection. They are the the major antigens that drive recognition of cells as as foreign or damaged or dangerous.

[00:29:04]And if uh these MHC molecules are different between the tumor and uh the cells of the mouse, then the immune system of the mouse will recognize the tumor as as foreign and will be eliminating the tumor. But if uh the tumor cells have the same MHC molecules as the mouse, then the mouse will or the immune system of the mouse will usually accept the tumor and the tumor can grow.

[00:29:32]And the first so the left part is all usually the case in in also our clinical patients because the tumor cells arise from our own uh cells and they have the same MHC molecules on their surface as as all the other cells in your body and therefore also usually the tumor cells have the same MHC molecules which makes it way way harder for the immune system to recognize them as as dangerous.

[00:30:00]Finally, um you can also use an immunocompetent mouse. So, it has an immune system. It has hair. That's why it's black and not pink. And then the immune system of the mouse will usually uh recognize the tumor cells and will eliminate them before they can form a tumor.

[00:30:20]So if the immune system is now so good at identifying tumor cells and killing them, why do some patients and a quite big portion of our population then develop tumors over time? And this is explained by the socalled 3 model and I would like to explain this to you now.

[00:30:43]So imagine you have a a cell in your body that has one of these mutations and turns into a cancer cell. These cells usually are somehow different than um the cells in in your body and they maybe express some some molecules over express some molecules. We will look at this in more detail in one of the next slides which allow for example NK cells to recognize them as foreign and they will kill them and also CD8 positive cytoxic T- cells T- killer cells can recognize them together with the help of antigen presenting cells and CD4 T cells and kill kill these cells at early stages of of tumor formation or cancer development and this happens in all our bodies all the time. So there are always a few cells that that have have a damage in their genes and they are on the way to turning these cancer cells and they are found and eliminated all the time in your body uh so that you do not develop cancer all the time. However, by the action of the immune system, so the killing of the uh degenerated cells by the immune system puts pressure on them.

[00:32:00]So they they want to survive maybe and therefore uh as as I said they they change all the time because the genetic stability is not not guaranteed anymore due to these changes in the cell cycle.

[00:32:13]And these cells then accumulate additional mutations that maybe allow them to grow even faster to maybe wander around or maybe stop the production of the molecules that allows the immune system to recognize them as foreign and dangerous. And then there's always some cells that change and the immune system then maybe finds another way to kill them. And this is then the second phase.

[00:32:38]This is called the equilibrium where tumor variants arise that are more uh resistant to killing but still the immune system can somehow control this tumor.

[00:32:51]And then there is the one or two uh very important mutations for the tumor that allow then the tumor to escape the immune system by either controlling the immune system. You see here uh this this tumor has induced this gray T- cell.

[00:33:08]It's a regulatory T- cell that can then suppress the immune system. So this takes off the pressure and also you see some of the tumor cells have maybe accumulated mutations that allow them to to wander away to other parts in your body, maybe your brain where they are more protected from from the immune system. And this is then the escape where the the tumor or the tumor cells can spread more or less unchallenged.

[00:33:35]And this these are the three E. Yeah.

[00:33:37]The first is the elimination which happens in all of us. Then there is the equilibrium where there is a constant fight but no none of the sides is winning and then at the end there is the escape where the tumor has has taken over.

[00:33:53]Unfortunately uh this is something we see all the time in patients that are immunosuppressed where the immune system is suppressed you can go from from elimination equilibrium to escape rather fast. So we see this Frequently in patients that get an organ transplant because they maybe have a kidney disease, they get a new kidney and in order to prevent the rejection of the kidney, they take strong immunosuppressants that that immune system doesn't destroy the new kidney. And then also this total process, this whole process is disrupted by suppressing the immune system and then you go from maybe equilibrium to escape within a few weeks and you develop a tumor that was controlled before rather efficiently. Yeah. So this is the 3 model, a very important model in tumor biology.

[00:34:49]One quick slide to how cancer is diagnosed. So imagine you have you have a patient female one with a breast cancer and you want to learn more about the tumor and how to how to fight it. So the first thing you do is you take a biopsy. So you take a small sample from the tumor and you look at these cells because as as you can probably imagine every tumor and every patient is somehow different. So everybody has has different mutations and every tumor has different properties and it makes it like an individualized thing to to treat the tumor efficiently and then two things are done. The first one is called hisytologology and there you take the the sample or part of the sample you you extract it from the patient and you look at it under the microscope and if you are an expert in hisytologist you do this all the time and you can see how far uh the cells have come from turning from normal body cells into these cancer cells. And here you see my my crude depiction of different states of degeneration. And you uh can then already judge okay this this is still very close to the original situation or this is very far ahead and probably has also spread to other parts of your body.

[00:36:09]Then you also take some some DNA from your cells and you do genetic analysis and there you look which protoonco genes have turned into enco genes and this tells you a lot about the the properties of the tumor. So what does it need to grow? How fast will it grow? how how likely it is to form for example metastasis. So there a lot of uh information is known and if you put these informations together you know okay this is a a tumor that is pretty far along in his journey of degeneration and maybe this this over expresses a receptor called her two. This is a receptor for for certain hormones which is very typical in breast cancer. And then you know okay this is a her two positive breast cancer and then you know okay maybe uh I have to treat this one by blocking the her two receptor and then you have certain certain drugs that block the her two receptor and then you can treat this kind of tumor pretty efficiently whereas the tumor is if the tumor is a breast cancer that doesn't hurt too you can treat the tumor all day long with these drugs against her two and it will have no effect. So this is what we call a stratified therapy.

[00:37:23]Um because we treat the tumor according to what it is and not essentially to where it was found. So if if you have like a a metastasis of a breast cancer in your colon, uh it might still be hard to positive. Uh so we need to treat it as as the breast cancer that it once was but not as as a colon cancer maybe.

[00:37:47]Okay. And this this can be done as I said with antibodies and the most famous one is called trstusumab.

[00:37:54]Okay.

[00:37:57]Now after giving this this general overview about tumor biology, I know I said in the beginning it's it's a rather broad overview. we will turn to how the immune system uh usually recognizes tumors and how we can use the immune system to control and treat these cancerous diseases. And the most important problem we have and that you need to understand is that the tumor is mostly self tissue. So the tumor once was a normal cell in your body and as we have learned in one of the previous lectures there is something that we call tolerance development. So your immune system learns what is normal in your body and it learns to basically ignore all the normal cells in your body because if it wouldn't it would kill you all the time. This is what happens in autoimmune diseases. Your immune system recognizes your own cells and tissues as as foreign and dangerous and then it starts to destroy these tissues and if these tissues are important for you then you will get sick and maybe die. And the same is true for tumors. they are mostly self tissue. They shouldn't be uh eliminated by the immune system. But now these cells have changed but maybe not enough to be recognized as as foreign and dangerous. And this is a big problem.

[00:39:16]So how does the immune system normally recognize tumors and cancerous cells? So here for example you have a tumor that is growing and some cells will always die during this process will be damaged and uh then parts that are normally in the cells also come out and these can be recognized by so-called antigen presenting cells and they recognize tumors for example via these tumor antigens that are released from the tumor cells and they bind to antibodies IGT antibodies that are recognized via so-called FC gamma receptors. These are antibodies that that act as adapter molecules. Then the cells take up and they maybe induce immune responses by presenting tumor antigens.

[00:40:03]Tumors can also be recognized by scavenger receptors or cype lectin receptors. These are pathn recognition receptors that usually recognize pathogens by structures that do not exist on our own cells. And for example, as we will see in one of the next slides, certain sugar structures are over expressed on on tumor cells that we would normally find on for example bacteria or fungi and this can allow the immune system to recognize these cells as dangerous.

[00:40:35]Then there can also be direct interaction. So the antigen presenting cells scans the surface of uh the cancer cells and there it can find antibodies that might have bound. uh it can find complement proteins and it can recognize these carbohydrates also directly on the surface of the cell. If this happens and an immune response is initiated, the tumor uh would be would be eliminated.

[00:41:02]But if the this system does not work, the tumor would would escape. This is one of the ease in the 3D model.

[00:41:10]However, if this recognition works, then usually uh antigen presenting cells will induce naive T- cells. They turn intoector cells that activate B cells and together these cells usually destroy the tumor. So this is what we call imunological surveillance.

[00:41:30]This is an example just an example you can directly forget it. There are many different types of cype lectin receptors on the surface of the antigen presenting cell that recognize different sugar structures.

[00:41:43]Also, I do not know most of them, but the ones that I put in bold letters are the ones that are overexpressed on certain tumors, whereas the the ones that are that put in gray are usually structures that we find on pathogens.

[00:41:58]You see there are very specific uh carbohydrate motifs that can be changed in these tumor cells which allow them the cells to recognize the tumors. And you see there also different types of antigen presenting cells. Ones are called uh conventional droidic cells. This is the gray part and one are some are called plasma denitic cells. These are the the pink ones and they differ at least in part in their expression of the C type lectin receptors.

[00:42:30]Okay. Besides the expression of these danger molecules that we normally find on pathogens, the tumors also release some some proteins, some factors that have usually nothing to do with with pathogens, but they can still activate the immune system. And these are called DMPS damage associated molecular patterns. And some examples are the high mobility group protein B1. Some heat shock proteins, some ATP that is normally inside the cells or uric acid that is normally inside the cells. But once the cells are damaged, this this stuff comes out and can be recognized triggering again an activation of T- cells. And these DMPS are also called alarmments because they allow alert the the immune system towards a point of damage, point of tumor development, maybe also a a wound that you have uh where these things, these molecules are then released from the cell and this uh can then initiate and drive meaning perpetuate non-infectious inflammatory diseases. So there is no pathogen around therefore it's non-infectious but still you find a immune response that is initiated. If we now look at um the induction of immune responses by the tumor, you can see that the activation of the T-C cells by these antigen presenting cells requires the presentation of tumor derived peptides so small fragments of tumor derived proteins to the T- cell receptor via the MHC molecules of the antigen presenting cells. And this in in end effect determines the specificity of the tumor cells. So they will only be activated if the T- cell receptor matches that peptide and the other way around only T cells that recognize these these tumor peptides will be activated but not all the other for example pathogen specific T- cells.

[00:44:37]Let's look at these these antigens. There are different classes that I want to go through with you and they are called tumor rejection antigens. So these are the antigens that lead to the induction of T- cells and the T- cells then destroy the tumor. That's why they called tumor rejection antigens and they are uh different classes. The first class are so-called neoepitopes. So neo means new and epitope is that the part of the protein that is presented. And these are new versions of normal proteins that uh only exist if you have a tumor. And this is pretty easy to understand if you think about the first first example I brought the uh Philadelphia chromosome with the BCR able fusion protein. And then part of the BCR is fused to parts of this uh ABLE protein and then a new peptide will be generated as maybe half of the BCR protein and half of the able protein and this is something that does not exist outside of tumor cells. So these antigens are strictly tumor specific and therefore this is not part of the tolerance development and then T- cells can be activated that recognize this P uh this this antigen.

[00:45:52]Then we have something that we call cancer testus antigens. These are proteins that are normally only expressed in male germ cells. So sperm cells but they are maybe overexpressed in melanoma. So cancer of of the skin or breast cancer.

[00:46:08]Then we have differentation antigens.

[00:46:10]These are genes or proteins encoded by genes that are expressed normally only in in certain types of tissues.

[00:46:17]Tyrosinase is as an example. This is strongly overexpressed in skin cancer. Then we have an abnormal gene expression. So certain certain genes are strongly overexpressed and the proteins are made in much higher numbers in tumor cells than in normal cells. And then this these cells uh turn into cancer cells. And one prominent example is her to new. Um this is then the example from the diagnosis I I told you before. This is a receptor for a growth factor that is strongly overexpressed in these breast cancer cells allowing these cells to bind more of the growth inducing factor and to divide even stronger.

[00:47:00]Then you have proteins that are abnormally post-transationally modified. So translation is the uh process of turning an mRNA into a protein and then there are certain modifications that happen after this. So post translationally so certain sugar molecules are added for example and these processes can be massively disrupted in in cancer cells and then you maybe have proteins that are strongly over glycosillated. So meaning they have much more of these sugar molecules. And then you can also have for example molecules that are not correctly glycosillated. And this happens for example in a a mucine protein a a protein in your mucus. So this is the the glib stuff in your lung for example. And if this is strongly under glycosillated it doesn't work. And then uh it can be recognized as as foreign and dangerous. Then you have abnormal post-t transanscriptional modification. So transcription means putting putting your your genetic information into an mRNA. And if there is for example additional formation included by the retention of in inrons in the mRNA this results in a change in protein sequence and then there is additional uh information in there or frame shifts happen that totally change the sequence and then you have um new peptides that can be generated from these proteins.

[00:48:31]And then there are lastly some some few examples where for example viruses like the human papilluma virus cause a transformation of infected cells and then they produce for example virus proteins that can be then overexpressed in in the infected cells if they turn into cancer cells.

[00:48:54]So how are tumor cells normally surveillanced and uh this is done by two types of cells the NK cells and the CD8T cells and we will start with the NK cells. So imagine you have you have a normal cell like like a liver cell is always my example that produces liver enzymes and this cell like most of your cells in your body then shows on its surface what it's working on on its inside. So it makes a lot of liver enzyme proteins and they are then also turned into peptides. So shorter fragments and these fragments are then presented on the surface of the cell on the MHC class1 molecule. So these cells continuously show on their surface what they work on in their inside.

[00:49:42]If the cell now turns into a cancer cell, it might be stressed because it realizes, oh, something is not not right with me. uh and then it sends stress signals that can activate the ENK cells and they can then kill the cell that is on the way to turning into a a tumor by secretreting molecules like perforinine that punches holes into the membrane of the cell and then proteasis and defenines go into the cell and and induce a program that we call apoptosis.

[00:50:14]So this is controlled cell death where the cell basically kills itself in a clean way that it can be recycled.

[00:50:22]This this action of the ENK cells can also then be enforced by cytoines. So small u molecules that transmit information for example by by macrofasages.

[00:50:36]But if the the cells are further along in their journey to becoming uh a cancer cell, they can also shut off the presentation of peptides and then they cannot be recognized as as dangerous anymore because the cell the ENK cell does not does not not realize them anymore but still they are they are killed. Yeah. And this is uh what we call the missing self theory that was awarded a a Nobel prize uh to professor sinagle in the 90s. And this works because the system is a bit more complicated. So here you have again a normal cell that shows these for example liver peptides on its surface and if the enk cell um scans the cell it gets basically two signals. The first one is it recognizes the liver peptides on the MHC molecules and then it knows for some crazy reason that is too complicated to explain at this point that this cell presents presents liver peptides. So it is a liver cell. So everything is is in order with that cell. So this transmits an inhibitory signal uh into the encaser. Basically the normal cell tells the enk cell everything is right in me please don't kill me and there is also an activating liant on the normal cell uh that rec is recognized by an activating receptor on the enk cell. So basically it's a bit bit crazy of the normal cell. It says on the one side everything is is all right with me please don't kill me on the other side it says something is is not right with me please kill me. Yeah. And if these signals are both there, both the inhibitory receptor and the activating receptor are engaged on the ENK cell, the ENK cell is somehow confused and does nothing.

[00:52:30]So the the cell can survive. But if either um the um inhibitory signal is gone, so the cell has stopped uh expressing these MHC molecules or the activating liant is gone. So that's that's that's the right example. So both signals are gone. It doesn't matter if only the uh the inhibitory one or the activating one is gone. The end result will always be that the inhibitory receptor is not engaged and uh the cell will be killed. So this is how K cells can then react to quite a broad range of of mutations in these cells if they change towards becoming cancer cells.

[00:53:16]So if we look at cancer cells, there is a a spectrum of these cells in terms of expression of a lot of molecules. And we will just look at MHC molecules. So there are cells that express high amounts of MHC, normal amounts of MHC, low amounts of MHC or maybe no MHC at all. And the immune system has come up with a very clever system. So the activation of ENK cells and the killing of the tumor cells by ENK cells depends on the level of MHC expression.

[00:53:52]And the lower the MHC expression is, the lower the signal is that is transmitted by the inhibitory receptor. So the lower the MHC expression, the more the cell, the ENK cell realizes that something is wrong with that cell and it will kill the cell and there's a certain threshold.

[00:54:09]And there are other cells which we will look at in in a second, CD8 positive cytotoxic tea cells that also can kill cancer cells. But there the system is the other way around. Yeah, these cells definitely need the signal via the MHC class1 to the T- cell receptor to recognize that oh this there's something wrong. because they need to to recognize these two more rejection antigens via the MHC and the T- cell receptor. And here they need a certain level of of uh peptide presentation via MHC.

[00:54:45]And then the more peptides are presented, the better the cell can kill uh the tumor. So there the threshold is the other way around. Yeah. And there's there's there are two different thresholds that that overlap uh in the middle making sure that for every level of MHC expression there is a cell that can can recognize the cell as as changed and dangerous and can try to kill it. So I think that's a very elegant very elaborate system that prevents uh many patients from developing cancer and this can be the system is true can be controlled pretty easily in or relatively easily in in experimental systems by for example transfecting cells with with MHC molecules then you make them more easily be killed by CD8 T cells or suppressing MHC expression in two more lines and then they are killed more easily by the NK cells. Alex had a question.

[00:55:47]>> You just explained it.

[00:55:49]>> Okay, that's that's what I'm here for.

[00:55:52]Okay, great.

[00:55:54]So, this is this is the missing self.

[00:55:59]Then um you or cancer cells can also be killed by a mechanism that is called ADCC antibbody dependent cell mediated cytotoxicity. It's like Stefan what are you talking about? So cytotoxicity means the cell is killed. Toxic is toxic and killing and cyto is the cell and antibbody means so the triggering factor that causes the cell to be killed is an antibbody and cell dependent means in the end the cell that is killed is killed by another cell. And what this means is basically that especially at at later stages of of tumor development there are certain antigens on the surface of the the tumor cell that are not expressed on normal cells for example different sugar structures. They are recognized by antibodies because the immune system has made a a B cell response against these antigens. And then these antigens act as adapter molecules that allow the ENK cell to recognize the cell as as dangerous and kill it. And this is very very important as we will see in in the last part of the lecture because these antibodies have in a way revolutionized the treatment of of cancerous diseases because they can be made in very pure forms in very big amounts to treat patients.

[00:57:23]Then um we have the recognition of these tumor rejection antigens these peptides from from proteins that are specific to tumors by the CD8 T- cell and they can then kill the T- cell by releasing perforin which again punches holes proteasis and granzy B which induces or together induce apoptosis.

[00:57:51]So as I said before tumor cells can be killed by these CD8 positive tea cells because we also call them cytotoxic tlymphosytes. That's what CTL means.

[00:58:04]They do this by transmarine but they also do it by uh a molecule that is called fast. F is called the death liant and it binds to a fast liant. These are both trime proteins. So they consist of three identical proteins next to each other and this transmits a very strong um signal towards the tumor cell to go into apoptosis.

[00:58:32]Besides the CD8 positive cytotoxic tymphocytes CD8 T cells that directly kill the tumor also we have other TE- cells in our body. These are called the CD4 positive dehelper cells. They are also very critically important in controlling uh immune responses towards cancer because they are the managers of the immune system that regulate all immune response and also activate the CD8 cells. They help establishing memory responses and in a certain capacity they can also directly kill cancer cells.

[00:59:07]They can secrete cytoines. So small molecules in the immune system and one of them is called tumor necrosis factor alpha. There you already have it in the name. It's a molecule that induces death in in tumors. Yeah.

[00:59:25]So if this system is so perfect, how can it happen that the tumors uh escape the immune system? And there are different different uh things that contribute to this. The first one is especially relevant in the initial phase of of tumors when they are still small.

[00:59:45]The first one is a low imunogenicity.

[00:59:48]You see there is a tumor cell. It doesn't release anything. No peptides that can be taken up by the antigen presenting cell. It doesn't trigger any path recognition receptors. So there is just nothing there for the immune system to work with.

[01:00:02]Then uh it can also happen that certain molecules are released from from the tumor. They are taken up by the antigen presenting cell but still the tumor doesn't trigger pattern recognition receptors or the damage associated molecular patterns are not there. So the cell is not activated and if the cell only presents peptides via MHC molecules but no co-millatory molecules and no cytoines the cell the T- cell that is specific for that that antigen will be tolered. So this will not result in T- cell activation and then also some tumors can change over time. You see it was an orange tumor cell it turns into a a purple tumor cell. So this is what we call antigenic modulation. And this uh happens if the immune system then starts to recognize the cell and starts to apply pressure on them. Yes, Alex.

[01:00:57]As tumor cells are cells from self um and the antigens are taken up by the dendritic cells and presented to te- cells.

[01:01:06]The dendritic cells um direct uh immune response against self proteins. Mhm.

[01:01:13]>> Could it be that after some time there is the initiation of um autoimmune reactions?

[01:01:24]>> That that is a fascinating question. Um I am not aware of it actually. Uh if this would happen, I don't know.

[01:01:32]>> I also never heard about it. So it just came into my mind.

[01:01:35]>> It is it is uh it's a relevant point but I'm not aware of it. So somehow the immune system must must control against it or >> seems like >> seems like it or >> or we need to go into literature.

[01:01:50]>> Yeah. But I think there are there are unfortunately there are so many patients around with cancer uh and if a a big portion of them would develop autoimmune diseases we would have probably heard about it. So um yeah in the end you still have tolerance development going on all the time. It probably eliminates most of them. Yeah.

[01:02:11]>> Yeah.

[01:02:11]>> Yeah. But f fascinating question.

[01:02:14]>> Thank you.

[01:02:16]>> Okay. This this is rather easy to understand. Um now it gets a little bit more complicated but I'll do my very best. Um because at some point the tumor is not just hiding but it starts to fight against immune system. So it starts to modulate immune system. So you have a tumor cell in the middle that has certain molecules on its surface and certain molecules that it secretes and these little bush dots sorry for the strong words and they then regulate immune system and there are different molecules for example IDO that is a abbreviation for indole 23 deoxxygenase this is a molecule that inhibits tryptophane metabolism. Tryptophane is an essential essential amino acid. So the T- cells and all the cells that divide very strongly need a lot of um tryptophane and this idol then blocks tryptophane metabolism and basically the the cells the tea cells then starve and then they can't start immune responses.

[01:03:27]Then you have TGF beta transforming growth factor beta. This is a cytoine that the immune system normally uses to shut down immune responses at the end of an immune response. And this is then also secreted by by tumor cells. So basically they shut down the immune system and via certain molecules for example antigen presentation via MHC and certain co-inhibitory molecules the tumor cells can induce their own regulatory tea cells. So these are cells also normally part of your repertoire in your immune system to shut down immune responses at the end of uh an an infection or to prevent autoimmune diseases and these then produce more idol more TGF better and also interlucan 10 which uh inhibits the activation of the tea cells.

[01:04:20]So I said the tumor can induce uh the differentation of regulatory T- cells via the expression of cointory molecules and coin inhibitory molecules. You see here a dendritic cell that activates a T- cell and you see that there is a lot of communication going on between the antigen presenting cell the denotic cell and the T- cell. So in the middle you have the the MHC with the peptide that gets recognized by the T- cell receptor and then whether this the cell which is specific via its T- cell receptor to that that peptide is activated or not depends on the additional signals it gets and this is done by the mixture of co- stimulatory molecules which transmit an activating signal into the T- cell and co-inhibitory molecules which tell the cell basically no no this I'm presenting a peptide here but this is totally normal. normal please don't start immune response it's a important control mechanism in your body to prevent the establishment of autoimmune diseases and you see there are there are quite some examples quite complicated just that you have seen it here and you can see for example CD80 and CD86 are very important co- stimulatory molecules uh on the dendritic cell and they can be recognized either via CD28 for example on T- cell that results in T- cell activation or CTLA4 on the T- cell then it results in inhibition and the CTLA4 has a much higher affinity so it binds much stronger to um CD8 and CD86 uh than CD28 and this can result for example in that T- cells are not activated if they are instructed for example by tumor cells to strongly upregulate CTLA4 then for example a postular signal can no longer be recognized by that cell.

[01:06:18]Here you see a a clinical example of of a patient that has a gastric cancer. So cancer in the gastrointestinal system and on the left side you see a a normal healthy control and on the right side you see uh this this gastric cancer. You see the the tissue looks quite a bit different and there are a lot of these blue cells in there and these are regulatory T- cells. So there's a strong accumulation of regulatory tea cells in later stages of cancer. And these cells then suppress the immune system. They do this by secretreting certain cytoines.

[01:06:54]I'm not going to go into into all of the details of that slide. If you want to look at it, you can press pause. But the most important ones are TGF beta transforming growth factor beta IL 10 and VGF uh vascular endothelial growth factor.

[01:07:10]And they can suppress for example T- cell growth, T- cell differentiation, they inhibit cytoine secretion, they induce energy in the T- cells. So they suppress T- cells being activated. They can inhibit antigen presentation, shift the type of immune response that is going on down regulation of co stimulatory molecules and induction of more regulatory cells. So there is a a massive potential in these cytoines that is used by the tumor to modulate the immune system.

[01:07:40]So besides the modulation of the immune system by the tumor also some tumors form something that we call a tumor induced privileged site. So do you see this tumor has formed its its own barrier, its own house, its own castle made of collagen and then the immune cells maybe cannot reach the tumor anymore and then it can can grow happily within this tumor induced privileged side.

[01:08:08]Okay. So now that we understand how the immune system normally fights cancer and uh how the tumor evades recognition by the immune system, we want to look at the last part of the lecture how we can use the immune system to fight cancer and this is as I said in the beginning where the revolution in cancer uh treatment is going on at the moment.

[01:08:35]So what is the aim in in curing cancer or treating cancer? It requires that all malignant cells are either removed or destroyed from the patient. That's very easy. You can just irradiate the patient uh with a very high dose of irradiation and then all the cancer cells will be dead. The problem is all the other cells will also be dead. Yeah. So you have to do it without killing the patient under ideal circumstances and this this makes it very difficult.

[01:09:08]We could talk like three four five six lectures about uh tumor treatment but to make it very simple and to be able to focus on u the ammonological part I've made this this slide. So the the goal is always to reduce tumor load. So to get rid of much as much of the tumor as possible and this is usually done by this cascade. So the first one is surgery. So if you find a tumor try to cut out as much as possible.

[01:09:38]Sometimes sometimes that's rather easy.

[01:09:41]Sometimes it's it's more difficult because if the tumor is is at some some site in your body that is that is massively important or if it's near to some arteries or if it's in your brain then you can't cut out that much. If you've done so however then you try or start to treat the patient with uh radiotherapy or chemotherapy.

[01:10:03]So under ideal circumstances you have cut out all of the tumor with the surgery but you cannot be sure. So there could be single cells still around at at the tumor site or some maybe have have spread already to other parts of your body and you try then to eliminate them um with either chemical substances that destroy cells that strongly divide. This is for example cancer cells but also immune cells or cells in your stomach. This is what we call chemo chemotherapy or radiation therapy. So you apply uh radiation to kill the cells. This is either done on the whole body. Usually not. Usually it's done for example uh towards the chest uh if if the patient has a breast tumor. And this can then be repeated and either done at the same time. So maybe give a localized radiotherapy uh towards the chest in in patients with with breast cancer. and then they get systemic chemotherapy or just one or the other. Uh there are millions of combinations and this usually leads um towards such a strong reduction of the tumor load um that you cannot find uh the tumor cells anymore in the patient but they might still be around a few cells that could then start new tumors. This is then where imunotherapy is is initiated. Then we try to use the immune system by the strategies I'm going to tell you in the next slides by killing the last few remaining tumor cells. So at this point I would like to ask the two of them if they have any idea when these these types of treatments were first performed. Do you have any idea when could the first surgery have been done? the first radiotherapy, chemotherapy, amunotherapy.

[01:11:58]Yeah. Ho.

[01:12:01]>> So, I would say surgery is fairly old.

[01:12:05]>> Mhm.

[01:12:05]>> I think >> I don't know, but I would guess like >> maybe even medieval times. I don't know.

[01:12:12]>> Even before. So, we have we have found mummies from the Egyptians that were treated with with surgery. So, it's before >> Oh, even Okay. So, before Christ.

[01:12:21]>> Yeah. before Christ radio therapy would be very new.

[01:12:25]>> Yeah, like that's very new.

[01:12:27]>> Any idea about radio or chemotherapy?

[01:12:32]>> Somewhere in between.

[01:12:33]>> Yeah, somewhere in between. Alex, >> I would say in the No, it's the English word for >> Yeah. 19th century.

[01:12:44]>> 19. No, no, it's 18th century.

[01:12:46]>> 18th century.

[01:12:47]>> Say, >> okay. I mean closer to way closer to the imunotherapy than to the surgery.

[01:12:54]>> Yeah.

[01:12:54]>> Mhm.

[01:12:55]>> 19th 19th century 18.

[01:12:58]>> Yeah. Something something like this. So um as I said surgery we found found evidence that it was done by the Egyptians on mummies. Radiotherapy was started in 1896. It's crazy. This is where where runken and and colleagues were discovering the runken radiation.

[01:13:16]And then you could go to your to your local party uh at your at your at your village at your town and you could could get your hand uh irradiated by renken uh apparatus and see the bones. And this was like a party trick where many people developed cancer from later on. And uh chemotherapy is something that was started during second world war and imunotherapy was started in the 1970s. So uh this is a rather new development but you can see uh we are making we are making progress.

[01:13:51]So what are the aims of of imunotherapy?

[01:13:56]So you have a tumor and you want to get rid of the tumor and you want to do so in imunotherapy when tumor load is low you remember the last slide by providing the patient with anti-tumorectors imunologically. These can be antigen presenting cells. These can be faceto tea cells or this can be uh antibodies. And ideally uh you would not give this from the outside because this is this is difficult and expensive to make. But ideally you would trigger the immune system of the patient to do this by his or herself. Yeah. So you want to stimulate the patient's own anti-tumor responses.

[01:14:35]There are five things that that are done uh that I want to quickly go through with you. And the first thing are immune system modulators. And here the goal is to just give a boost to the immune system to start immune responses. So you want to break the tolerance of the immune system towards the tumor that the tumor has has induced.

[01:15:00]And this is done by giving cytoines.

[01:15:02]Cytoines, as I said multiple times already, are small messenger molecules that uh transmit in this case an activating information to uh the immune cells in your body and the two most famous ones are interlocking 22 and interferon alpha and they both promote the activation of tea cells. They are used for metastatic so cancer that has already spread melanoma. uh so this is skin cancer and renal cell carcinoma this is like kidney kidney cancer they they activate immune system but this is not without side effect so this causes death in 2% of the patients is not so good yeah it's a rather high rate of death I would not like that as as a side effect and this is caused by uh something that we call capillary leak syndrome so what happens is you inject huge amounts of these these cytoines to trigger the immune system. That's exactly what they are doing. And they do this by changing for example the permeability of the cells in your blood vessels and that immune cells can can migrate over the the the the blood vessels into the tissue and then also a lot of fluid and other cells migrate into the tissue and this can this can cause a lot of a lot of damage and loss of blood pressure and something like this. Interferon alpha induces MHC1 expression on on tumor cells. You make them more killable uh by the NK cells and the CD8 T cells and it enhances the activation of dendritic cells, macrofasages and also the NK cells and the T- cells. This is done then again for for melanoma patient a renal cancer patient but it causes n neuroprocsychiatric diseases and uh changes your your brain basically damages your brain because the cells are activated very strongly and some of them obviously go into the brain and cause a little bit of damage there and it then can also cause autoimmune diseases. Maybe this is a bit uh into the direction of Alex Alex question and uh it can destroy your thyroid gland.

[01:17:16]Then you develop something that is called hypothyroidism. So your your thyroid gland is damaged and your your metabolism basically tanks and goes uh goes down way way uh stronger than it should and it can also cause vitiligo and this is uh where I brought you two clinical examples. So, vitiligo is an autoimmune disease that destroys the melanocytes in your skin and in your hair. And the melanocytes are the the cells that give your skin the color. You see on the left side, you maybe remember him. That's Michael Jackson, very famous musician. On the right side is is a famous famous model that I don't remember the name of because I'm not into models. Um but you see they have these white spots on their skin and this is uh caused uh either by cancer treatment on the right side or by some also inherited disease probably in Michael Jackson.

[01:18:13]Nobody knows. Um and therefore these these melanocytes are destroyed. The skin turns turns very white. This is only a cosmetic problem. So nothing is wrong with your skin. It's just white.

[01:18:26]But of course you you can imagine this causes some some problems for the the affected persons.

[01:18:34]Then uh the second strategy is something that we called therapeutic vaccines or maybe even prophylactic vaccines and this was initiated by results again from from mouse models where you take a mouse you immunize it with killed irradiated tumor cells and this mouse will not develop a tumor. But then if you take the same mouse and inject it with live tumor cells that would normally result in tumor formation, this mouse also doesn't develop a tumor. And this means if you think about it that this mouse with the first application of the irradiated tumor cells has made an immune response that can protect it from the live tumor cells.

[01:19:15]And if you I know it's it's a mean model then take the same mouse and give it a different tumor and not the one that that was irradiated in the first place then it will develop a a tumor. So this is a specific response that can be induced towards a certain tumor. Yes Hannah >> is this what they do with the cervical uh cancer vaccine?

[01:19:38]>> Yes. Yes. Because this is this is caused by human papilloma viruses. And uh if you immunize young children both male and female against these these viruses, they will form immune responses and then you will prevent that these uh viruses can infect them and cause the transformation of uh normal cells into uh tumor cells in in the female child.

[01:20:07]Yes, Alex.

[01:20:08]But then in theory it would be possible to just just create a vaccine that um includes like the tumor markers we were talking before like her two for example and uh create vaccines against or create one vaccine against many tumor markers.

[01:20:29]Would this be possible?

[01:20:30]>> In theory uh we will come to this in a point. This would be possible. The problem is yes her two is a very very frequent frequent antigen in certain tumors but it's just one and many um tumor cells have developed multiple mutations and then even if you treat one maybe there are other factors that are changed in these cells and you you will see it's very hard to to hit all of them and every patient is different and that makes it makes it quite a bit different that's also why this was done in a in a certain way as I will tell you on the next slide >> and I can imagine that if you have no tumor but you um vaccinate against um these kind of proteins maybe then we have the autoimmune disease we were talking about before >> that that is that is maybe a complicating problem and also I think in our modern society many people will not understand why they should be vaccinated against 100 different antigens that are self in a way. Yeah.

[01:21:36]>> Yeah.

[01:21:37]>> But yeah, in theory as you will see this works. So how is this done? This is called adoptive TE-C cell therapy. So what you have is you have a patient with a tumor that gets treated with surgery and radiation. So again we are in the immunotherapy stage where the tumor load should be pretty low.

[01:21:58]Then you isolate some tea cells from from the patient that are tumor specific. So there are there there has been an immune response initiated but it is suppressed by the tumor. Then you give strong stimula that activate these T- cells like interlocking 2 you know from from the first strategy but you do it now outside of the body and uh some anti-CD3 that that activated T- cells and you have some antigen presenting cells and then you give it back and then you hope that these activated fight ready tea cells then attack the tumor.

[01:22:33]This is this can be done uh but you have also the chance that you activate some some non-tumor cells in there and therefore usually you take some tumor biopsy which is taken anyway during the surgery and you add then this tumor cellizate and maybe some some aduants that trigger an even stronger T- cell activation that you rather specifically activate than the T- cells that are really specific for the tumor. Yeah, this this was done. Uh there was one product on the market. I took out the slide. Um it is a a a vaccine against prostate cancer. It worked. Uh but it improved the survival of these these prostate cancer patients by only four months and it cost like €100,000.

[01:23:21]That's why that's why it's not available on the European market anymore because there the health insurance has to pay and it's not not financially viable in the US. It's still on the market because there you pay for your own treatment and then people are maybe willing to pay this for the four months.

[01:23:38]So yes or no.

[01:23:43]So basically there is the vaccine like for example for the cervical cancer that you give in advance. So it's um >> prophylactic >> prophylactic. So basically there's a prophylactic type of vaccine like for the cervical cancer >> and there is a vaccine that you give when the patient already has cancer >> therapeutic >> made from their own cells.

[01:24:09]>> Yeah. Yeah. So that's that's exactly true. prophylactic you give before you even have the cancer and then there's therapeutic when the patient already has cancer. And this is of course much more difficult because then all the modulation has happened. The cancer is maybe already several months or years old and has done all kinds of damage in your body and in your in your immune system.

[01:24:33]The advantage here is you don't have to think about things like hystocompatibility.

[01:24:40]So are this the T- cells compatible with with the specific patients? Because they always are in this in this setting because they come from that patient.

[01:24:50]Yeah, you take the patient's own cells and then uh give them back. But this also makes it more complicated because you have to do this for every patient.

[01:24:58]Yeah, that's why it was so expensive.

[01:25:00]you have to take patient blood, isolate the T- cells in a uh rather sophisticated very well controlled lab, activate them and then ship them back and inject them into the patient. So that's why it is so complicated.

[01:25:15]Yeah. Um so in a way these vaccines are designed to stimulate the immune system of of the patient but the problem is that the tumors are poorly imunogenic.

[01:25:26]So they don't want immune responses to be induced against them and they are difficult to develop because uh as we just discussed there are many different antigens that vary from tumor to tumor.

[01:25:38]Tumor peptides can only be presented if you have the matching MHC molecules. You can produce all the tumor peptides all all the time you want but if they do not fit in your MHC molecules then it doesn't help you because then the immune system can't be activated. And to make them effective, you must probably include a lot of different different tumor antigens. And therefore, this can only be used when when the the tumor burn is very low. What might work better uh there Alex and Hana who are too smart for uh my lecture structure is something that we call prophylactic vaccination.

[01:26:20]So this is now worked on uh quite extensively and I think here for example mRNA based vaccines are a a huge opportunity because there you can can generate these different tumor antigens or the sequences of these tumor antigens very easily. So what you do is you vaccinate the patient, you induce an immune response against the tumor antigen and he forms then these anti-tumor uh killer cells that do nothing as long as the tumor is not around. But then if the patient later on after the vaccinations can be months and years later develops the tumor, it can be killed in really early stages by these anti-tumor cytotoxic tea cells and then you will never even realize that you were on the way to developing cancer. But as we discussed before this uh has has a lot of of problems because there are many different tumor antigens that you need to be aware of and um there is the chance of inducing autoimmunity.

[01:27:24]The third strategy that uh from now on the things will be very uh successful.

[01:27:30]So strategies 3, four and five is what's what's revolutionizing uh tumor tumor therapy already at the moment are so-called therapeutic antibodies. This is a big group of drugs. Therapeutic antibodies are in a way drugs that are used to instruct the immune system to attack the tumor or to attack the cancer cells.

[01:27:54]The thing is um they then act as adapter molecules to activate immune system but they can only usually be used against tumor specific antigens that are expressed on the surface of the tumor because usually the antibbody does not go inside the cell. So you need to have structures on the surface of the cancer cell that can be bound by the antibbody to have its effective function. And there are different types. They are usually monocclonal antibodies. This means they are derived from one uh B cell that was turned into an immortal antibbody producer. So it's a clone and it only produces one antibbody that's therefore it's a monoconal.

[01:28:39]So these are very defined molecules.

[01:28:42]Then uh you can modify these these antibodies. You can either act a toxin that then kills the cell that binds the antigen or you can add a source of radiation. So you can have like a small let's let's call it small radiation uh substance radiating uh small atomic reactor if you want to call it like this that then transmits radiation and kills the cell that is bound by an antibbody.

[01:29:11]And then you can also improve these antibodies by just using antibbody fragments. So the the upper part of the antibbody is called a fap fragment and they are much smaller and therefore they can penetrate much deeper into the tumor tissue and they can also be modified then with toxins or radiative substances.

[01:29:30]So how do they do they work? They can either directly kill the tumor when binding to the antigen, for example, by the irradiation or by the toxin. And the toxins are uh cleverly designed. They only are toxic um if the cell takes them up. Uh the antibbody then it gets activated inside the cell and the cell will die. Whereas the ones with irradiation just kill everything that is around.

[01:29:58]Then you have antibodies inducing this antibbody dependent cell mediated cytotoxicity. Here the antibbody just acts as an adopter molecule allowing the ENK cells to uh recognize the cancer as foreign. And then you can also have the antibodies used as tools to trigger the compliment system and basically this results in poor inclusion of in thetumor cells and the tumor cells that will then bleed out and be destroyed.

[01:30:27]Then you have certain tumors that need to be vascularized. So they need their own or need to form their own blood vessels so that they can be can be fed by by the rest of the body. And then there are antibodies that can prevent this vascularization like the anti-VGFR receptor or the anti-intreen alpha beta 1 alpha 5 beta 1 that then basically help to starve the tumor.

[01:30:53]How do they work? They can further also inhibit uh the drizzation of receptors.

[01:31:01]For example, you remember the heruh receptor in this breast cancer patient.

[01:31:06]It is a dimer. So it consists of two um proteins that need to come together to form an an active receptor. And if you block um one of these molecules, it cannot associate with the other one. And therefore there is no functional receptor and the cell can no longer react to the growth stimulus. Then you can block the ligant that bind to the receptor and uh you can just cross-link the receptor and use a very strong activating signal that is so strong that the cell decides oh no no no no this is all looking a bit shady I just go into apoptosis there are different target molecules for these antibodies again I will not go uh into detail you can press pause it's uh it's it's quite complicated but there are anti antibodies against uh for example CD20 then you can kill all the all the B cells there are antibodies against glyoproteins there are antibodies against these angioenic molecules so the against processes that lead to the formation of blood vessels you can inhibit growth or differentation signaling or you can target specific glyolippids and carbohydrates.

[01:32:19]Carbohydrates are sugars. Glyolippids are molecules consisting of sugar and fat like structures and then you can specifically kill or recognize tumor cells.

[01:32:33]Problems with these terapotic antibodies is they are very good at killing tumor cells but only sometimes the outer shell. Yeah. And then you have a lot of dead cells and debris and the the the antibodies just do not get deep enough into the the pulsating heart of the tumor if you want to call it like this and you only kill kill or damage the outer shell. This can be improved by using smaller antibbody molecules but if you have a big tumor there are patients with tumors that are like this big you can imagine it's very difficult for the antibodies to reach into the whole uh tumor mass.

[01:33:10]Then there there is inefficient killing.

[01:33:12]You see there are two tumor cells that where the the antibbody cross links the receptor. It's the same same thing happening on both cells. One gets so strongly activated that is uh goes into apoptosis but the other one just doesn't react to the signal. So this is inefficient killing. And some tumors uh are swimming in a in a sea of their own debris and then the antibodies are mopped up by soluble antigens so that they don't even reach the tumor or don't reach the tumor in sufficient amounts.

[01:33:49]Okay, these are the therapeutic antibodies and now we come uh to the immune checkpoint modulators.

[01:33:57]So what does this refer to? This refers to what we learned in the beginning that the tumor modulates the immune system by all these mechanisms. And uh to make it more simple, it's it's a rather complicated process. I've made this this slide. So imagine you have a T- cell that is specific for a tumor and it has two choices. If it's a cytotoxic T- cell, it can either kill the tumor, that is the lower part, or it can ignore the tumor and the tumor can continue with its growth. So that's the upper part and this is controlled by additional signals that the T- cell gets. So if the T- cell gets instructed by an antigen presenting cell via presentation of tumor peptides and coilatory molecules, it can get an activating signal. Then it will kill the tumor.

[01:34:54]But if it gets for example a deactivating signal via these co-inhibitory molecules um then it can be instructed by the tumor for example to ignore the tumor and then the tumor will survive and this is done by many different signals. The two most famous ones are um on this the the T-C cell side the CTLA4 and the PD1.

[01:35:20]PD is a programmed death one and it binds to PDL1 programmed death lian one or two and the CTLA4 is also a co-inhibitory molecule that binds to CD80 and CD86 and this way of the tumor suppressing the T- cell response can be regulated by antibodies and there are two very famous antibodies that are anti-PD1 and anti-CTLA4. These are antibodies that bind then to PD1 or CTLA4 and therefore they block these receptors and then the tumor can no longer instruct the T- cell to ignore the tumor. So you modulate how the tumor modulates the immune response. So basically you make the T- cell more uh easy to activate and then it will no longer ignore the tumor but it will start killing the tumor.

[01:36:21]>> Yes, Alex.

[01:36:23]>> But I can imagine a lot of side effects in this case right because you have the high uh inflammation of tea cells like >> undirected to the tumor but directed to everything.

[01:36:36]>> Yes. Yes. Basically that's that's that's exactly true. There is a threshold at which TE- cells are activated and you now start by or the tumor the tumor started that fight. Let's let's be let's be real for a moment. The tumor increase the threshold. So it says no no no we first started immunospants very late and now you come in with the antibodies and you lower the threshold making the T- cells more easily again to be activated and this causes a lot of problems. Yeah, you lower the threshold for T- cell activation making TE- cells more easy uh activatable but this also results in in a lot of uh inflammation because this is not specific to the antitumot cell. This happens in all the tit cells and then you will form like autoimmune responses and inflammatory responses.

[01:37:28]This is exactly what's happening. So there are different antibodies u available in the clinics. uh one is called epilimum map. It targets CTL4 and it works miraculously one has to say. So here is a clinical example on the left side you see a patient or different patients with tumors always there where you have the white arrows there there's there's a tumor. So you have one in in in the in the lung on top also a little bit further down in lung you have you have quite a few small tumors and you also have one in the brain. So this especially the one in the brain would be very difficult to to get out with surgery without doing too much damage. And then the same patient was treated with the antiCDLA4 antibbody and you see also the big tumor on the top and the tumor in the brain they are gone. Yeah it's it's it's crazy. So uh you can uh treat patients with this antibbody and 20% of patients with these treated with these antibodies have survived advanced melanoma for more than four years and they would have died with 100% certainty without the antibbody. So and there are there are data that some of these patients survive for 10 years. So you could could define them as cured from their cancer. But as as Alex already alluded to, uh you start to mingle with the immune system and you get a very strong activation of the immune system which you use to kill the tumor, but you also get uh damage in in the rest of your body. And this is from the same patient. You can see um the first the upper most one is uh a biopsy of the skin, then of the gut and of the liver. And you can see all these small blue points, they are lymphocytes, TB cells that have invaded the tissue looking for uh some thing to kill and they cause a lot of cause a lot of inflammation and this is what we call immune related because the immune system is activated offtarget because it targets something else than the tumor and toxicity because it it causes damage. Yeah. And this is of course something you might not feel very good with as a patient. Yeah. And you have to imagine that the the patients that are treated with this, they have they have cancer.

[01:39:53]They are not the fittest. And this this can be a problem. Yeah.

[01:39:57]So there are these these severe life-threatening side effects like global skin uh inflammation gastrointestinal inflammation damage to the to the kidney and the liver and this is like in 24% of treated patients and uh this is this is of course something that you have to then again treat against and then you give for example steroids to block the immune system or antiTnf antibodies to to uh to tone down the immune response.

[01:40:28]Yeah. Uh so nothing is without its side effect and therefore it's it's very difficult at the moment to to judge how much needs to be done. Yes. products.

[01:40:39]>> Do you know how long these side effects um stay? Because when the antibbody is gone like after 21 days, half time um it should be reduced afterwards or >> Yeah. So, so the halflife of these antibodies is 21 23 days. So, I would say that yeah, you give high amounts of these antibodies. So it will not be completely gone after 22 days but maybe after 100 days it will be done. Yeah.

[01:41:12]Doesn't matter because the patient will not survive that long. So they get these these offtarget toxicities and then they get treated within days usually because otherwise they would die. Yeah. Okay.

[01:41:22]>> So you start this this initial immune response but at some point you have to stop it. It's not like you wait until this >> goes away by itself. If you have this high degree of T- cell activation or B cell activation then you have to stop it.

[01:41:35]>> Okay. Thank you.

[01:41:36]>> Okay.

[01:41:37]There are two other drugs that target PD1. One is called Pembbritzumap. The other one is called Neo Lumap uh by different companies. All are intended to treat patients that would die otherwise like that have advanced melanomaomas or skin cancer that has spread to the whole body or non small cell lung cancer is also very difficult to treat or metastatic renal carcinoma. the PD1 the antiPD1 antibodies seem to work a little bit better. So there the response rates are like 10 to 50%. So it means 10 to 50% of treated patients will do much better with these antibodies and only 10% of patients develop these these adverse effects. So yeah um this has led to a lot of clinical studies. So these are numbers from 2020 where there were just just 334 studies going on and in in 2024 it's already 1,350 studies going on. So there is an intensive uh interest in further developing these checkpoint inhibitors. But this these drugs have challenges as Alex already alluded to.

[01:42:52]So we don't know do we actually need these strong immune responses are only the tumor sufficiently killed if you have these strong immune responses or can you directly give them with for example some some steroids and it still works then the question is how can they be safely combined with existing and novel treatments for example with I don't know uh the the cancer vaccines or the cartis cells that we will look at in a minute How strong of an immune response do we need and how long should we treat?

[01:43:26]That's exactly Alex's question. So this is just things we don't know and we have to try and at the moment we are learning the hard way. We were learning this by by using this and patients which have no other choice. Yeah.

[01:43:37]Okay. Then we will we will round up today's lecture with the last strategy that is even more I think promising.

[01:43:47]It's the uh CT cell therapy. Car is is not a car that you drive around with.

[01:43:54]It's a chimeriic antigen receptor.

[01:43:57]What is this? So you in this strategy use so-called CAT T cells. And if we look at this more closer, so if you have a T- cell that is specific for a tumor and in order for the T- cell to kill the tumor, you need to activate it. And this is done uh in immonology by the T- cell recognizing a peptide specifically by its T- cell receptor. This transmits then an activating signal into the nucleus of the T- cell telling it to become activated. But this is rather weak in terms of signal and you need this this peptide doesn't come from nowhere. It's not swimming around it.

[01:44:39]It's presented on the surface of an antigen presenting cell that has taken up the tumor antigen processed it into a peptide and presents it via MHC plus2. So they need two cells basically and then you have the antigen present presenting cell also providing co- stimulatory molecules which then give a much stronger activating signal into the nucleus of that T- cell and only if these all these things and signals and cells and stuff comes together you can get an activation of the T- cell.

[01:45:14]However, there's an easier way for the immune system to be activated because our immune system has structures that can directly recognize for example tumor antigen and these are antibodies and they even uh can can react to pep peptides but they usually react to the the intact molecules. So you don't even need the whole antigen presentation for this. They can directly react to correctly folded proteins. they can directly react to also sugar structures.

[01:45:45]And what was now done is they have generated a Frankenstein receptor by fusing the top part of an antibbody that recognizes the antigen with a spacer.

[01:45:58]It's usually a CD8 molecule and uh intracellular parts that transmit an activating signal and this then can directly uh result in the activation of a T- cell. So you basically have improved the T- cell by introducing a receptor that can directly activate the T- cell. But again before Alex raises her hand, you have also eliminated the control by the antigen presenting cell. Yeah. So these cells once they see their antigen, they will start the fight. Yeah. So this can of course again result in in problems and the the intracellular parts of this car cell transmit even stronger activating signals and this would result in if you have these CAT tea cells in in patients that they efficiently recognize the the tumor and can directly kill it without the help of any other cell.

[01:47:01]There are different generations of cars.

[01:47:04]The first generation of cars did not have um the sequences inside that are needed to transmit the coastal military signal. This is then for the second generation we have these domains as they are called like 41B or CD28 or in the third generation we have even multiple uh of these um co similar domains. day. The first generation still needed a co- stimulation from an antigen presenting cell or from some kind of other signal. The second and the third generation of cars are fully self-sufficient in activating the D celler.

[01:47:44]What then happens I don't want to go too much into detail is that once the antigen is bound on the outside, it triggers all kinds of activating signals in in the T- cells. If you are interested in this, you can press on pause. There are a lot of different molecules that probably will not tell you anything. Some some might say something to Alex and Hana because they are like an advanced stages of their their PhD uh thesis. But basically what they all do is they trigger different transcription factors in the nucleus of the T- cell that then allow the T- cell to become fully activated and fight uh that cancer.

[01:48:25]Um, just one small clinical example. I think it's a groundbreaking study. It's a little bit old, but it was like the first one. It was a CAR directed against CD19. CD19 is a molecule that is expressed in most B cells and it was used in patients that have acute lymphoplastic leukemia. So they have a cancer where their B cells have turned into cancer cells and they then cause so much trouble and destruction that they kill the patients over time and then these patients were treated with CAR T cells that uh were direct against CD19 and out of 30 patients in 27 uh of them that's 90% all signs of cancer disappeared. That's crazy. It's like 90% that the cancer is gone and before CARTT cell treatment most of them would have died and out of these 27 patients 19 have remained in remission. So they are basically cured from cancer and uh 15 out of these 19 uh received no further therapies. So only four of them uh needed some some other kind of treatments. And these are like response rate and treatment success rates that were unthinkable before. And now we can treat certain kinds of cancers with these cells that would have killed the patient in 100% of the cases before.

[01:49:49]How is this done technically? So you have a patient with a tumor. You isolate some tea cells u by for example taking some blood. Then you stimulate them in in vitro. So in petri dishes in in the laboratory you activate them with all kinds of factors like interlocking 2 is the one we learned about in in the first strategy that activates the te- cells and then you transfect them with certain viruses.

[01:50:19]So you use viruses that infect the T- cells to basically transmit the plan how to build the the cartisel receptor into the the genome into the nucleus of that cell and then it will start making the car receptor make antigen receptor. Then you you give them some rest because this is a stressful event and some cells also die during that procedure. And then you maybe uh treat them very well. uh send them into the the recreation hotel to uh expand them uh to get sufficient amounts and then you infuse them back into the patient and they can start killing uh the tumor.

[01:51:02]Problem is you have basically T- cells that can be activated antigen specifically now compared to to the strategy before but they cause very strong immune responses and then uh this causes diseases like cytoine release syndrome. So you will feel very sick be when these if these cells uh secrete a lot of of cytoines and many patients secrete high amounts of interlucan 6 as a strongly inflammation inducing cytoine and this this has sometimes has then to be blocked again with steroids and anti- interalucin 6 molecules which are also available in the clinic because they are used for for autoimmune diseases for example and then depending on what your target is. You have to be careful because if you treat these uh lymphoma patients with the antiCD19 car, you have killed all their B cells. So they will be cured but they will be immunos deficient afterwards because you have killed all their B cells. So you need then to provide them either with some some new B cells or give them some antibodies or some antibiotics to to make them again immuno competent at least to a certain degree. And you can also see here this is again the numbers for for clinical uh studies on CT cells.

[01:52:21]Uh it is again quite a high number of these studies showing that this probably has has a lot of promise. So if you come to the end I've brought you here like a a slide I modified uh from from a textbook. It's not important what is on the slide but what is important is to realize that there were some breakthrough things discovered like in the last last century then there were some even more things discovered in the last century and then in this century alone in the last in the first 25 years we have made tremendous progress by just understanding how our cancer development works understanding how the immune system can control cancer and we have made really tremendous progress. So this that I think that many of the the cancerous diseases that are a big problem or were a big problem will not be that much of a problem and maybe they will turn into chronic diseases that you can live can live with rather normally.

[01:53:23]>> The best time to have cancer is now >> h or in 10 years probably.

[01:53:29]>> Yeah, of course.

[01:53:30]>> Yeah. Yeah. It's that's what Hana is saying. So of your lifetime the best time to have cancer is now.

[01:53:37]>> Yeah. So if you would have had leukemia 30 years ago you would have died day you might be cured. Um so if you come to the summary um cancer is a disease caused by an uncontrolled division of abnormal cells in your body and this is then triggered by certain stimuli that um turn these protoonco genes that normally regulate for example the cell cycle into enco genes and then the cell cycle is running uncontrollably allowing these cells to to uh grow uncontrollably. and to spread in your body. Yeah. And this is normally controlled by the immune system with the 3E model that that eliminates usually the tumors. But some tumors then then escape and they then start to modulate the immune system by for example inducing these regulatory T- cells also pressing T- cell responses by themselves.

[01:54:38]Tumor treatment is done by a cascade of surgery followed by radiotherapy and chemotherapy. And then when the tumor load is low, we do imunotherapy to eliminate the last few tumor cells.

[01:54:51]And then we have made tremendous progress in the last two three decades with um inducing two anti-tumor responses that discriminate between tumor cells and their normal counterparts. And here especially the therapeutic vaccines might be might be a big big changer in future but especially the therapeutic antibodies now already are a big game changer and the checkpoint modulators and CT cells are also very very good with this I would ask the two of them if they have any further questions I know it's it's a a difficult topic because we all know people that have had cancer or have cancer at the moment but at least we try to give you some information that you can understand what's going on and how and why these diseases are treated in a way they are. Okay, there are no further questions. I thank the two of them again really uh for for doing this with me because they also find a lot of times where I talk just gibberish and then they correct me and then we can we can have this in in a way that that is maybe good for you to understand. If you two out there have have questions, just post them in the comment section. We try to get back as you as fast as we can. And uh with this uh I thank you all for watching and we see you in the next video. Bye >> bye.

[01:56:27]>> The title says tumor iminology.

[01:56:30]Oh, Hana is too smart and she can read the stuff. She has good eyes.

[01:56:37]>> I think um it's because we are playing so many riddle games.

[01:56:42]>> Mhm.

[01:56:44]>> Isn't our job a big riddle game? Isn't life a big riddle game?

[01:56:49]>> Actually, >> but it's so hard to find the ways >> that we switch to English.

[01:56:56]>> We have no other choice.

[01:57:07]Okay, Alex, you need another chair at some point.

[01:57:12]>> So, I can change my chair now if you want. Then it's no problem anymore.

[01:57:17]>> Yeah, change your chair.

[01:57:19]>> Yeah, now. Okay.

[01:57:20]>> Uh, >> okay. I will get an >> It's It's not going to happen. It's not going to happen today. Everybody's running away.

[01:57:29]>> No, if she >> No. Yeah. Yeah.

[01:57:32]>> If she's quick, then it's a H. She's She's leaving the room. Okay.

[01:57:37]>> Go your freedom to get a tea.

[01:57:42]>> We use the phrasal verb go off to mean that the sound is beginning to go. Okay.

[01:57:50]It shows that a sudden and spontaneous noise had started. Ah, okay. I'm sorry.

[01:57:55]Sorry, I was not aware of this.

[01:57:57]>> English learning with Alex.

[01:58:00]Take two.

[01:58:01]>> You never said this in the last 8 years, so it's your fault.

[01:58:06]>> Because I was talking English.

[01:58:12]>> Okay. Again, then there is the second checkpoint. It's at the end of the G0 phase. So the S has then uh decided >> again T0.

[01:58:22]>> G0. What is wrong with me? What is wrong with me? I'm a Gzero guy. Obviously, all of iminology happens in Gzero phase.

[01:58:32]So that's >> Yeah, but all the cancer stuff is happening between S and G1.

[01:58:40]>> Okay.

[01:58:41]>> Or not all, but >> most but it's it's okay so far.

[01:58:47]Okay, cool. Okay. Okay. Okay.

[01:58:52]Yeah. What?

[01:58:54]>> I have internet problem.

[01:58:57]>> But Hannah Hannah's controlling me.

[01:58:58]Yeah. Okay.

[01:58:59]>> Yeah. I I think I will just um turn off the computer again and come in again.

[01:59:07]>> Okay.

[01:59:07]>> I hope this will fix it.

[01:59:09]>> Continue. Yeah.

[01:59:10]>> Yeah. Yeah. Or you make a PP break.

[01:59:13]>> Not Not yet.

[01:59:15]>> Not yet. Okay. Then see you soon.

[01:59:17]Hopefully.

[01:59:18]>> See you soon.

[01:59:21]that can be used to attack the pathogen or to instruct the immune system to attack. No, that can be used.

[01:59:31]Not the pathogen. It's a tumor.

[01:59:36]It's a t. It's a trap.

[01:59:38]>> Attack the tumor.

[01:59:40]>> It's a trap.

[01:59:41]>> Yeah, actually it is.

[01:59:43]>> Yeah. Yeah. Alex, you can clap. Alex has has graduated successfully from Clapping University.

[01:59:52]Okay.

[01:59:53]>> Doctor degree in angel studies.

[01:59:55]>> Angel Oh, angel studies. That sounds interesting.